title: Apoptotic photoreceptor loss and altered expression of lysosomal proteins in the nclf mouse model of neuronal ceroid lipofuscinosis.
abstract: OBJECTIVE
  Mutations in the CLN6 gene cause variant late-infantile neuronal ceroid lipofuscinosis, a lysosomal storage disorder clinically characterized by progressive loss of vision, dementia, seizures, and early death. Here, we analyzed the time course of photoreceptor loss and the role of lysosomes in nclf mice, an animal model of the human CLN6 disease.
  
  
  METHODS
  Labeling of apoptotic cells, activated astrocytes, and Müller cells, and expression analyses of glial fibrillary acidic protein, rhodopsin, and lysosomal proteins were performed on nclf mice during the course of retinal degeneration. In addition, the distribution and variability of storage material was examined at the ultrastructural level.
  
  
  RESULTS
  Progressive apoptotic loss of photoreceptor cells was observed in nclf mice, resulting in reduction of the outer nuclear layer to approximately 3 rows of photoreceptor cells at 9 months of age. Onset of reactive gliosis was observed in 1-month-old nclf mice. Ultrastructural analysis revealed lysosomal storage material containing curvilinear and fingerprint-like inclusions in various retinal cell types. Expression levels of soluble mannose 6-phosphate-containing lysosomal enzymes, such as cathepsin D and the lysosomal membrane protein Lamp1, were increased in retinal cells of nclf mice.
  
  
  CONCLUSIONS
  Accumulation of heterogeneous nondegraded macromolecules in dysfunctional lysosomes and autolysosomes impairs photoreceptor cells, ultimately leading to early-onset apoptotic death with subsequent activation of astrocytes and Müller cells in the retina of nclf mice. The defined steps of photoreceptor degeneration suggest that nclf mice might serve as an ideal animal model for experimental therapeutic approaches aimed at attenuating vision loss in neuronal ceroid lipofuscinosis.
authors.affiliation: Department of Ophthalmology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Udo
authors.initials: U
authors.lastname: Bartsch
authors.forename: Giovanna
authors.initials: G
authors.lastname: Galliciotti
authors.forename: Guillermo F
authors.initials: GF
authors.lastname: Jofre
authors.forename: Wanda
authors.initials: W
authors.lastname: Jankowiak
authors.forename: Christian
authors.initials: C
authors.lastname: Hagel
authors.forename: Thomas
authors.initials: T
authors.lastname: Braulke
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D008247:Lysosomes / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008854:Microscopy, Electron; D009472:Neuronal Ceroid-Lipofuscinoses / Q000378:metabolism / Q000473:pathology; D010786:Photoreceptor Cells / Q000378:metabolism / Q000473:pathology; D011506:Proteins / Q000378:metabolism*; D013997:Time Factors
chemical_list: C486722:Cln6 protein, mouse; D008565:Membrane Proteins; D011506:Proteins; C018589:lysosomal proteins
keywords: CLN6; cathepsin D; lysosomes; mannose 6-phosphate; neuronal ceroid lipofuscinosis